Methods for treating neuropsychiatric disorders

ABSTRACT

The invention provides methods for treating neuropsychiatric disorders such as schizophrenia, Alzheimer&#39;s Disease, autism, depression, benign forgetfulness, childhood learning disorders, close head injury, and attention deficit disorder. The methods entail administering to a patient diagnosed as having a neuropsychiatric disorder a pharmaceutical composition containing (i) a therapeutically effective amount of D- or L-phosphoserine.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.09/291,296, filed Apr. 14, 1999, now U.S. Pat. No. 6,228,875, andprovisional application U.S. Ser. No. 60/081.645, filed Apr. 14, 1998.

BACKGROUND OF THE INVENTION

Schizophrenia, Alzheimer's Disease, autism, depression, benignforgetfulness, childhood learning disorders, close head injury, andattention deficit disorder are examples of neuropsychiatric disorders.Autism, for example, is a developmental mental disorder characterized byautistic behavior, social failure, and language delay. Alzheimer'sDisease is a form of dementia that typically involves progressive mentaldeterioration, manifested by memory loss, confusion, and disorientation.Alzheimer's Disease typically is treated by acetylcholine esteraseinhibitors such as tacrine hydrochloride or donepezil. Attention DeficitDisorder is a disorder that is most prevalent in children and isassociated with increased motor activity and a decreased attention span.Attention Deficit Disorder commonly is treated by administration ofpsychostimulants such as Ritalin or Dexedrin. Depression is a clinicalsyndrome that includes a persistent sad mood or loss of interest inactivities, which persists for at least two weeks in the absence oftreatment. Conventional therapeutics include serotonin uptake inhibitors(e.g., PROZAC™), monoamine oxidase inhibitors, and tricyclicantidepressants.

The term schizophrenia represents a group of neuropsychiatric disorderscharacterized by dysfunctions of the thinking process, such asdelusions, hallucinations, and extensive withdrawal of the patient'sinterests from other people. Approximately one percent of the worldwidepopulation is afflicted with schizophrenia, and this disorder isaccompanied by high morbidity and mortality rates.

Conventional antipsychotic drugs, which act on the dopamine D₂ receptor,can be used to treat the positive symptoms of schizophrenia, such asdelusion and hallucination. In general, conventional antipsychotic drugsand the new atypical antipsychotic drugs, which act on the dopamine D₂and 5HT₂ serotonin receptor, are limited in their ability to treatcognitive deficits and negative symptoms such as affect blunting (i.e.,lack of facial expressions), anergia, and social withdrawal.

SUMMARY OF THE INVENTION

The invention derives from the discovery that neuropsychiatric disorderscharacterized by a deficit in neurotransmission via the NMDA receptorcan be alleviated by a compound that acts as an agonist of the glycinesite on the NMDA receptor or an inhibitor of glycine uptake. Thecompound is either a partial agonist such as D-cycloserine, which can beused at a dosage of 105-500 mg, or a full agonist (e.g., D-serine orD-alanine) that is selective for the NMDA receptor (compared to theinhibitory glycine receptor and other receptors), or a glycine uptakeinhibitor (e.g., N-methylglycine). The invention therefore provides newmethods for treating neuropsychiatric disorders in patients (i.e.,humans). Examples of disorders that can be treated by the methods of theinvention include schizophrenia, Alzheimer's Disease, autism,depression, benign forgetfulness, childhood learning disorders, closehead injury, and attention deficit disorder. The methods entailadministering to a patient diagnosed as suffering from such aneuropsychiatric disorder a pharmaceutical composition that contains atherapeutically effective amount of an agonist of the glycine site ofthe NMDA receptor or a glycine uptake inhibitor, which agonist isrelatively selective for (a) the glycine site of the NMDA receptor,compared with (b) the inhibitory glycine receptor and other receptors.The pharmaceutical composition may include, for example, (i) atherapeutically effective amount of D-alanine (wherein thepharmaceutical composition is substantially free of D-cycloserine)and/or (ii) a therapeutically effective amount of D-serine, and/or (iii)D-cycloserine in an amount of 105-500 mg, and/or (iv) a therapeuticallyeffective amount of N-methylglycine.

In variations of the methods described herein, D-serine, D-alanine,D-cycloserine, and/or N-methylglycine can be substituted with a salt,ester, or alkylated form of the amino acid, or a precursor of the aminoacid that is converted (e.g., metabolized) into the amino acid in vivo(e.g., D-phosphoserine, L-phosphoserine, or L-phosphoserine,N,N,N-trimethylglycine (betaine), or N,N-dimethylglycine).

Typically, a dosage of 100 μg to 100 g (e.g., 1 Mg to 100 g; 1 mg to 100mg; 10 mg to 100 g; 10 mg to 10 g; or 10 to 500 mg) is suitable forD-alanine, D-serine, and N-methylglycine. D-cycloserine is administeredat a dosage of 105 to 500 mg. When the patient is treated with bothD-serine and D-alanine, D-serine and D-alanine can be administered tothe patient simultaneously or sequentially, e.g., by formulating theD-serine and D-alanine as a single pharmaceutical composition or as twoor more pharmaceutical compositions. Likewise, the patient can betreated with both D-serine and D-cycloserine, or D-serine andN-methylglycine, or D-alanine and N-methylglycine, or D-cycloserine andN-methylglycine simultaneously or sequentially. In one, but not theonly, suitable method of treatment, the pharmaceutical composition isadministered to the patient at least once daily for at least one week.If desired, the pharmaceutical composition can be administered to thepatient in more than one dose per day (e.g., 2, 3, or 4 doses).Generally, the patient is treated for at least one week; typically, thepatient is treated for at least several weeks (e.g., at least 4, 6, or 8weeks) or months (e.g., at least 4, 8, or 12 months). If necessary, thetreatment can continue indefinitely to keep the patient's symptoms undercontrol throughout his or her life.

If desired, a pharmaceutical composition containing D-alanine(substantially free of D-cycloserine), D-serine, D-cycloserine and/orN-methylglycine (or a modified version thereof, as described herein) canbe administered to a patient suffering from schizophrenia along with, orin sequence with, an art-known drug for treating schizophrenia (e.g.,olanzapine, clozapine, haloperidol, and the like). Similarly, D-alanine(typically substantially free of D-cycloserine), D-serine, D-cycloserineand/or N-methylglycine (or a modified version thereof, as describedherein) can be used in combination with, or in sequence with, otherart-known antipsychotics (e.g., “typical,” “atypical,” and depotantipsychotics for treating schizophrenia and other psychoticconditions), antidepressants (for treating depression), psychostimulants(for treating attention deficit disorder, depression, or learningdisorders), or Alzheimer's disease therapeutics (for treatingAlzheimer's disease). Such pharmaceutical compositions are includedwithin the invention. In general, the antipsychotic, antidepressant,psychostimulant, or Alzheimer's disease therapeutic typically isadministered at a dosage of 0.25-5000 mg/d (e.g., 5-1000 mg/d)).“Typical” antipsychotics are conventional antipsychotics such asphenothiazine, butryophenones, thioxantheses, dibenzoxazepines,dihydroindolones, and diphenylbutylpiperidines. “Atypical”antipsychotics are a new generation of antipsychotics which generallyact on the dopamine D₂ and 5HT₂ serotonin receptor and have high levelsof efficacy and a benign extrapyramidal symptom side effect profile.Examples of typical antipsychotics (and examples of suitable daily (d)dosages) include Chlorpromazine (5-2,000 mg/d, e.g., 30-800 mg/d),Thioridazine (5-2000 mg/d, e.g., 20-800 mg/d), Mesoridazine (1-1000mg/d, e.g., 30-400 mg/d), Fluphenazine (0.5-200 mg/d, e.g., 1-40 mg/d),Perphenazine (0.5-300 mg/d, e.g., 10-65 mg/d), Trifluoperazine (0.5-200mg/d, e.g., 2-40 mg/d), Thiothixene (1-200 mg/d, e.g., 6-60 mg/d),Haloperidol (0.25-500 mg/d, e.g., 1-100 mg/d), Loxapine (1-1000 mg/de.g., 20-250 mg/d), Molindone (1-1000 mg/d, e.g., 15-225 mg/d),Acetophenazine (10-2000 mg/d, e.g., 30-500 mg/d), Chlorprothixene(5-2000 mg/d, e.g., 30-500 mg/d), Droperidol (0.25-500 mg/d, e.g., 1-100mg/d), Pimozide (0.25-500 mg/d, e.g., 1-100 mg/d). Examples of atypicalantipsychotics (and examples of suitable daily dosages) includeClozapine (5-2000 mg/d, e.g., 12-900 mg/d), Risperidone (0.25-500 mg/d,e.g., 2-16 mg/d), Olanzapine (1-100 mg/d, e.g., 5-10 mg/d), andQuetiapine (1-2000 mg/d, e.g., 50-750 mg/d). Depot antipsychotics alsocan be used, e.g., Haloperidol decanoate (10-1000 mg/month, e.g.,100-450 mg/month), Fluphenazine decanoate (5-1000 mg/month, e.g., 25-150mg/month), and Fluphenazine enanthate (5-1000 mg/month, e.g., 25-200mg/month). Additional antipsychotics include Butaperazine (0.5-500 mg/d,e.g., 1-200 mg/d), Carphenazine, (0.5-3000 mg/d, e.g., 1-1000 mg/d),Remoxipride (0.5-5000 mg/d, e.g., 1-2000 mg/d), Piperacetazine (0.5-500mg/d, e.g., 1-2000 mg/d), Sulpiride (0.5-5000 mg/d, e.g., 1-2000 mg/d),and Ziprasidone (0.5-500 mg/d, e.g., 1-200 mg/d). Examples ofantidepressants that can be used include Amitriptyline (5-1000 mg/d,e.g., 50-300 mg/d), Amoxapine (5-1000 mg/d, e.g., 50-600 mg/d),Bupropion (5-1000 mg/d, e.g., 200-450 mg/d), Bupropion SR (5-1000 mg/d,e.g., 150-400 mg/d), Clomipramine (5-1000 mg/d, e.g., 25-250 mg/d),Desipramine (5-1000 mg/d, e.g., 100-300 mg/d), Doxepin (5-1000 mg/d,e.g., 75-300 mg/d), Fluoxetine (1-200 mg/d, e.g., 20-80 mg/d),Fluvoxamine (5-1000 mg/d, e.g., 50-300 mg/d), Imipramine (5-1000 mg/d,e.g., 75-300 mg/d), Maprotiline (5-1000, e.g., 75-225 mg/d), Mirtazapine(1-200 mg/d, e.g., 15-45 mg/d), Nefazodone (5-1000 mg/d, e.g., 200-600mg/d), Nortriptyline (5-1000 mg/d, e.g., 75-150 mg/d), Paroxetine (1-200mg/d, e.g., 10-60 mg/d), Phenelzine (1-500 mg/d, e.g., 5-90 mg/d),Protriptyline (1-200 mg/d, e.g., 15-60 mg/d), Sertraline (5-1000 mg/d,e.g., 50-200 mg/d), Tranylcypromine (1-200 mg/d, e.g., 30-60 mg/d),Trazodone (5-1000 mg/d, e.g., 150-600 mg/d), Trimipramine (5-1000 mg/d,e.g., 5-300 mg/d), Venlafaxine (5-1000 mg/d, e.g., 75-375 mg/d), andVenlafaxine XR (5-1000 mg/d, e.g, 75-225 mg/d). Psychostimulants thatare particularly useful for treating attention deficit disorder includeDextroamphetamine (0.5-200 mg/d, e.g., 5-40 mg/d), Methamphetamine(0.5-200 mg/d, e.g., 5-25 mg/d), Methylphenidate (0.5-200 mg/d, e.g.,10-40 mg/d), and Pemoline (5-500 mg/d, e.g., 37.5-112.5 mg/d). Examplesof Alzheimer's disease therapeutics that can be used in the inventioninclude Donepezil (0.5-200 mg/d, e.g., 1-100 mg/d) and Tacrine (0.5-1000mg/d, e.g., 10-500 mg/d). Thus, the invention also providespharmaceutical compositions that contain D-alanine (typicallysubstantially free of D-cycloserine), D-serine, D-cycloserine and/orN-methylglycine (or a modified version thereof, as described herein)along with an antipsychotic, antidepressant, psychostimulant, orAlzheimer's disease therapeutic.

If desired, one can measure negative and/or positive and/or cognitivesymptom(s) of schizophrenia before and after treatment of the patient. Areduction in such a symptom indicates that the patient's condition hasimproved. Improvement in the symptoms of schizophrenia can be assessedusing the Scales for the Assessment of Negative Symptoms (SANS) orPositive and Negative Syndrome Scale (PANSS) (see, e.g., Andreasen,1983, Scales for the Assessment of Negative Symptoms (SANS), Iowa City,Iowa and Kay et al., 1987, Schizophrenia Bulletin 13:261-276). Likewise,one can measure improvement of other neuropsychiatric disorders inpatients who have been treated by the methods of the invention.

As used herein, the term “neuropsychiatric disorder” refers to a diseasehaving a pathophysiological component of attenuated NMDAreceptor-mediated neurotransmission. Examples of such disorders includeschizophrenia, Alzheimer's disease, autism, depression, benignforgetfulness, childhood learning disorders, close head injury, andattention deficit disorder.

As used herein, the term “schizophrenia” refers to a psychiatricdisorder that includes at least two of the following: delusions,hallucinations, disorganized speech, grossly disorganized or catatonicbehavior, or negative symptoms. Patients can be diagnosed asschizophrenic using the DSM-IV criteria (APA, 1994, Diagnostic andStatistical Manual of Mental Disorders (Fourth Edition), Washington,D.C.).

The term “Alzheimer's Disease” refers to a progressive mentaldeterioration manifested by memory loss, confusion and disorientationbeginning in late middle life and typically resulting in death in fiveto ten years. Pathologically, Alzheimer's Disease can be characterizedby thickening, conglutination, and distortion of the intracellularneurofibrils, neurofibrillary tangles and senile plaques composed ofgranular or filamentous argentophilic masses with an amyloid core.Methods for diagnosing Alzheimer's Disease are known in the art. Forexample, the National Institute of Neurological and CommunicativeDisorders and Stroke-Alzheimer's Disease and the Alzheimer's Disease andRelated Disorders Association (NINCDS-ADRDA) criteria can be used todiagnose Alzheimer's Disease (McKhann et al., 1984, Neurology34:939-944). The patient's cognitive function can be assessed by theAlzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog; Rosenet al., 1984, Am. J. Psychiatry 141:1356-1364).

As used herein, the term “autism” refers to a state of mentalintroversion characterized by morbid self-absorption, social failure,language delay, and stereotyped behavior. Patients can be diagnosed assuffering from autism by using the DSM-IV criteria.

As used herein, the term “depression” refers to a clinical syndrome thatincludes a persistent sad mood or loss of interest in activities, whichlasts for at least two weeks in the absence of treatment. The DSM-IVcriteria can be used to diagnose patients as suffering from depression.

The term “benign forgetfulness,” as used herein, refers to a mildtendency to be unable to retrieve or recall information that was onceregistered, learned, and stored in memory (e.g., an inability toremember where one placed one's keys or parked one's car). Benignforgetfulness typically affects individuals after 40 years of age andcan be recognized by standard assessment instruments such as theWechsler Memory Scale (Russell, 1975, J. Consult Clin. Psychol.43:800-809).

As used herein, the term “childhood learning disorders” refers to animpaired ability to learn, as experienced by certain children. Suchlearning disorders can be diagnosed by using the DSM-IV criteria.

The term “close head injury,” as used herein, refers to a clinicalcondition after head injury or trauma which condition can becharacterized by cognitive and memory impairment. Such a condition canbe diagnosed as “amnestic disorder due to a general medical condition”according to DSM-IV.

The term “attention deficit disorder,” as used herein, refers to adisorder that is most commonly exhibited by children and which can becharacterized by increased motor activity and a decreased attentionspan. The DSM-IV criteria can be used to diagnose attention deficitdisorder.

The terms “D-serine” and “D-alanine” refer to the D isomers of the aminoacids serine and alanine, respectively. As D isomers, rather than Lisomers, these amino acids are not naturally found in proteins.

“Negative” symptoms of schizophrenia include affect blunting, anergia,alogia and social withdrawal, which can be measured using SANS (theScales for the Assessment of Negative Symptoms; see Andreasen, 1983,Scales for the Assessment of Negative Symptoms (SANS), Iowa City, Iowa).

“Positive” symptoms of schizophrenia include delusion and hallucination,which can be measured using PANSS (the Positive and Negative SyndromeScale; see Kay et al., 1987, Schizophrenia Bulletin 13:261-276).

“Cognitive” symptoms of schizophrenia include impairment in obtaining,organizing, and using intellectual knowledge which can be measured bythe Positive and Negative Syndrome Scale-cognitive subscale(PANSS-cognitive subscale) (Lindenmayer et al., 1994, J. Nerv. Ment.Dis. 182:631-638) or with cognitive tasks such as the Wisconsin CardSorting Test.

A “full” agonist of the NMDA receptor is a compound that produces amaximal response at full receptor occupancy.

A “partial” agonist of the NMDA receptor is a compound that produces alower maximal response at full receptor occupancy than do full agonists.

A “glycine uptake inhibitor of the NMDA receptor” is a compound thatinhibits the re-uptake of glycine and increases the availability ofglycine for the NMDA receptor (e.g., N-methylglycine).

The invention offers several advantages over many art-known methods fortreating neuropsychiatric disorders. For example, unlike manyconventional antipsychotic therapeutics, D-serine, D-alanine, andN-methylglycine can produce a desirable reduction in the positive,negative, and cognitive symptoms of schizophrenia. As shown by theexamples set forth below, clinically significant improvement can beachieved even with patients who are poorly responsive to treatment byconventional antipsychotics. In addition, no significant side effectswere detected after treatment of schizophrenia patients with D-serine,D-alanine, or N-methylglycine. In contrast, conventional antipsychoticstypically lead to tardive dyskinesia (irreversible, involuntary movementdisorder), extrapyramidal symptoms, and akathesia symptoms.

Other features and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

DETAILED DESCRIPTION

The invention provides methods for treating a patient diagnosed assuffering from a neuropsychiatric disorder having a deficit inneurotransmission via the NMDA receptor (e.g., schizophrenia,Alzheimer's Disease, autism, depression, benign forgetfulness, childhoodlearning disorders, close head injury, and attention deficit disorder).As described above, a variety of methods for diagnosing these disordersare known to those of skill in the art of clinical psychiatry, and anyconventional diagnostic method can be used in conjunction with theinvention.

The treatment method of the invention entails administering to a patientdiagnosed as having a neuropsychiatric disorder a pharmaceuticalcomposition containing a therapeutically effective amount of (i) anagonist of the glycine site of the NMDA receptor, which agonist isrelatively selective for (a) the glycine site of the NMDA receptor,compared with (b) an inhibitory glycine receptor or any other receptor,or (ii) a glycine uptake inhibitor. For example, suitable pharmaceuticalcompositions may include (i) D-alanine substantially free ofD-cycloserine and/or (ii) D-serine and/or (iii) N-methylglycine.D-serine and D-alanine are commercially available (e.g., from SpectrumQuality Products, Inc., Gardena, Calif.). Where D-alanine is used, thepharmaceutical composition is “substantially free” of D-cycloserine,meaning that the composition lacks D-cycloserine, or D-cycloserine isnot included at a level sufficient to have a statistically significanteffect upon the efficacy of the pharmaceutical composition, asdetermined by any method (e.g., by comparing PANSS and/or SANS scoresbefore and after treatment of the patient). In general, this means thatD-cycloserine is absent from the pharmaceutical composition or presentin an amount such that the patient receives less than 0.02 mg/day.

Treatment includes administering a therapeutically effective amount of acomposition containing D-alanine (substantially free of D-cycloserine)and/or D-serine and/or N-methylglycine to a patient in need of suchtreatment, thereby treating the neuropsychiatric disorder. Suchcompositions typically contain from about 0.1 to 90% by weight (such as1 to 20% or 1 to 10%) of D-alanine, D-serine, or N-methylglycine in apharmaceutically acceptable carrier. Regardless of the concentration ofD-serine or D-alanine in the pharmaceutical composition, D-serine and/orD-alanine and/or N-methylglycine is administered to the patient at adosage of 10 mg to 100 g. More typically, D-serine and/or D-alanineand/or N-methylglycine is administered at a dosage of 100 mg to 10 g.Generally, treatment continues for at least several weeks to severalyears or life-long as needed.

In an alternative method for treating a neuropsychiatric disorder in apatient, a pharmaceutical composition containing D-cycloserine in anamount equivalent to a dosage of 105 to 500 mg/day is administered to apatient in need of such treatment. For example, the dosage can be in anamount of 125 to 400 mg, such as 150 to 300 mg (e.g., 175 mg, 200 mg,225 mg, or 250 mg). D-cycloserine (D-4-amino-3-isoxazolidinone) iscommercially available from Eli Lilly, Inc. (Indianapolis, Ind.).Generally, treatment continues for at least one week and can continuefor several years or life-long as needed to control the patient'ssymptoms.

In all of the methods of the invention, D-alanine, D-serine, and/orD-cycloserine and/or N-methylglycine can be substituted with a modifiedversion of the amino acid, such as a salt, ester, alkylated form, or aprecursor of the amino acid. For example, the amino acid can be in theform of a sodium salt, potassium salt, calcium salt, magnesium salt,zinc salt, or ammonium salt. such salt forms of D-serine, D-alanine,N-methylglycine and D-cycloserine can be made in accordance withconventional methods (see, e.g., Organic Chemistry, pgs. 822-823,Morrison and Boyd, ed., Fifth Edition, Allyn and Bacon, Inc., Newton,Mass.). Other modified forms of D-serine, D-alanine, N-methylglycine andD-cycloserine also can be used in the methods of the invention. Forexample, the carboxy group of the amino acid can be converted to anester group by reaction with an alcohol in accordance with standardesterification methods (Id. at 841-843). For example, alcohols having1-20 carbon atoms can be used to produce an ester of D-serine,D-alanine, N-Methylglycine or D-cycloserine for use in the invention(e.g., methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-,sec-butyl-, tert-butyl-, pentyl-, isopentyl-, tert-pentyl-, hexyl-,heptyl-, octyl-, decyl-, dodecyl-, tetradecyl-, hexadecyl-, octadecyl-,and phenyl-alcohols can be used). In another variation, the amino groupof the amino acid can be alkylated, using conventional methods, toproduce a secondary or tertiary amino group by ammonolysis of halides orreductive amination (Id. at 939-948). For example, an alkyl group having1-20 carbon atoms can be added to the amino acid to produce an alkylatedamino acid (e.g., methyl-, ethyl-, propyl-, isopropyl-, butyl-,isobutyl-, sec-butyl-, tert-butyl-, pentyl-, isopentyl-, tert-pentyl-,hexyl-, heptyl-, octyl-, decyl-, dodecyl-, tetradecyl-, hexadecyl-,octadecyl- and phenyl-groups can be added to the amino acid).D-phosphoserine and L-phosphoserine are examples of precursors ofD-serine, and are commercially available (e.g., from Sigma Chemical, St.Louis, Mo.). N,N,N-trimethylglycine (betaine) and N,N-dimethylglycineare examples of precursors of N-methylglycine.

In all of the methods of the invention, appropriate dosages ofD-alanine, D-serine, D-cycloserine, or N-methylglycine (or modifiedversions thereof) can readily be determined by those of ordinary skillin the art of medicine by monitoring the patient for signs of diseaseamelioration or inhibition, and increasing or decreasing the dosageand/or frequency of treatment as desired.

The pharmaceutical compositions can be administered to the patient byany, or a combination, of several routes, such as oral, intravenous,trans-mucosal (e.g., nasal, vaginal, etc.), pulmonary, transdermal,ocular, buccal, sublingual, intraperitoneal, intrathecal, intramuscular,or long term depot preparation. Solid compositions for oraladministration can contain suitable carriers or excipients, such as cornstarch, gelatin, lactose, acacia, sucrose, microcrystalline cellulose,kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodiumchloride, lipids, alginic acid, or ingredients for controlled slowrelease. Disintegrators that can be used include, without limitation,micro-crystalline cellulose, corn starch, sodium starch glycolate andalginic acid. Tablet binders that may be used include, withoutlimitation, acacia, methylcellulose, sodium carboxymethylcellulose,polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose,starch, and ethylcellulose.

Liquid compositions for oral administration prepared in water or otheraqueous vehicles can include solutions, emulsions, syrups, and elixirscontaining, together with the active compound(s), wetting agents,sweeteners, coloring agents, and flavoring agents. Various liquid andpowder compositions can be prepared by conventional methods forinhalation into the lungs of the patient to be treated.

Injectable compositions may contain various carriers such as vegetableoils, dimethylacetamide, dimethylformamide, ethyl lactate, ethylcarbonate, isopropyl myristate, ethanol, polyols (glycerol, propyleneglycol, liquid polyethylene glycol, and the like). For intravenousinjections, the compounds may be administered by the drip method,whereby a pharmaceutical composition containing the active compound(s)and a physiologically acceptable excipient is infused. Physiologicallyacceptable excipients may include, for example, 5% dextrose, 0.9%saline, Ringer's solution or other suitable excipients. Forintramuscular preparations, a sterile composition of a suitable solublesalt form of the compound can be dissolved and administered in apharmaceutical excipient such as Water-for-Injection, 0.9% saline, or 5%glucose solution, or depot forms of the compounds (e.g., decanoate,palmitate, undecylenic, enanthate) can be dissolved in sesame oil.Alternatively, the pharmaceutical composition can be formulated as achewing gum, lollipop, or the like.

EXAMPLES

The following examples demonstrate that D-alanine, D-serine, andN-methylglycine each can be used to treat a neuropsychiatric disorder inpatients.

Patients

This study employed 37 patients who were diagnosed as havingschizophrenia. All patients fulfilled the DSM-IV diagnosis ofschizophrenia (APA, 1994, Diagnostic and Statistical Manual of MentalDisorders, Fourth Edition, Washington, D.C.). All of the patients alsofulfilled the criteria of primary deficit syndrome, with a SANS score ofmore than 40 (Kirkpatrick et al., 1989, Psychiatry Research 30:119-123;Andreasen, 1983, Scales for the Assessment of Negative Symptoms (SANS),Iowa City, Iowa). All of the patients were poorly responsive totreatment by other antipsychotic drugs, and had been kept on a stabledose of an antipsychotic drug for at least 3 months prior to enrollmentin this study.

Assessments

Several scales were used to assess the severity of the disorder in eachpatient. At the beginning of the study (i.e., the baseline), the PANSS,SANS, and Global Assessment Scales (CGI) were used. Each scale also wascompleted at the end of each 2-week period throughout the study. Theseassessments were performed by a psychiatrist who was blind to thetreatment assignment. The Wisconsin Card Sort Test was used to provide acognitive rating of the patients; in general, schizophrenic patientsperform poorly on this test. The Wisconsin Card Sort Test wasadministered only at the initiation of the study and at the end of the6-week study. To measure side effects, the Simpson-Angus Scale was usedto measure extrapyramidal symptoms (EPS; Simpson et al., 1970, ActaPsychiatrica Scandinavia Suppl. 212:11-19). The Abnormal InvoluntaryMovement Scale (AIMS) was used to measure dyskinesia (Simpson et al.,1970, Acta Psychiatrica Scandinavia Suppl. 212:11-19). The Barnes Scalewas used to measure akathesia (Barnes, 1989, Brit. J. Psychiatry154:672-676). The side effects of D-serine, D-alanine, andN-methylglycine treatments were assessed biweekly according to the UKUside effects rating scale (Scandinavian Society of PsychopharmacologyCommittee of Clinical Investigation: The UKU side effect rating scale:scale for the registration of unwanted effects of psychotropics. Acta.Psychiatr. Scand. 1987; Suppl. 334:81-94).

Treatment and Results

Using double-blind conditions, the patients were randomly assigned toreceive placebo (fruit juice), D-serine (30 mg/kg/day), D-alanine(60-100 mg/kg/day), or N-methylglycine (30 mg/kg/day) once a day bymouth for a period of 6 weeks. As indicated by the results shown inTable 1, treatment with D-serine, D-alanine, or N-methylglycine improvedthe schizophrenic symptoms and cognitive deficit of the patients. Morespecifically, treatment with D-serine resulted in a 21% reduction of thenegative symptoms (on the SANS scale), and it resulted in a 17%reduction of the positive symptoms (on the PANSS-positive subscale).Treatment with D-alanine resulted in an 11% reduction of the negativesymptoms and a 12% reduction of the positive symptoms. Treatment withN-methylglycine resulted in a 20% reduction of the negative symptoms anda 15% reduction of the positive symptoms. These reductions in thenegative and positive symptoms represented clinically significantimprovement. Treatment with each of D-serine, D-alanine, andN-methylglycine also improved cognition, as measured using thePANSS-cognitive subscale and the Wisconsin Card Sort Test. These resultsindicate that D-serine, D-alanine, and N-methylglycine are effective intreating schizophrenia even in patients who are poorly responsive totreatment by conventional antipsychotic drugs.

Using the UKU scale for rating side effects, no side effects were notedafter treatment with D-serine, D-alanine, or N-methylglycine. Inaddition, there was no newly emergent tardive dyskinesia or worsening ofextrapyramidal or akathesia symptoms. Thus, D-serine, D-alanine, andN-methylglycine offer an advantage over many conventional drugs fortreating schizophrenia in that they do not cause significant sideeffects.

TABLE 1 Effects of D-serine, D-alanine, and N-methylglycine Treatment onSchizophrenia Patients D-serine D-alanine N-methylglycine PlaceboClinical Symptoms Negative −21%* −12%* −20%* −1% Symptoms Positive −17%*−11%* −15%* 3% Symptoms CGI 4.8−>2.6* 3.9−>2.8* 4.2−>2.7* 4.5−>4.0Cognition Cognitive −12%* −11%* −12%* 1% symptoms WCST +0.9 +0.5* +0.7*−0.5 (category)* Side Effects EPS 1.4−>1.7 3.1−>3.1 2.1−>2.1 3.3−>3.4AIMS 0.3−>0.3 0.5−>0.1 0.4−>0.3 0.5−>0.9 Barnes 0.4−>0.8 0.4−>0.60.5−>0.6 0.9−>0.9 *Clinically significant improvement

Other Embodiments

It is to be understood that, while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the appended claims. Other aspects,advantages, and modifications are within the scope of the followingclaims.

What is claimed is:
 1. A pharmaceutical composition comprising (i) atleast one compound selected from the group consisting of D-phosphoserineand L-phosphoserine and (ii) a second therapeutic agent selected fromthe group consisting of antipsychotics, antidepressants,psychostimulants, and Alzheimer's disease therapeutics.
 2. Thepharmaceutical composition of claim 1, wherein the second therapeuticagent is an antipsychotic selected from the group consisting of typicalantipsychotics, atypical antipsychotics, and depot antipsychotics. 3.The pharmaceutical composition of claim 1, wherein the secondtherapeutic agent is selected from the group consisting ofChlorpromazine, Thioridazine, Mesoridazine, Fluphenazine, Perphenazine,Trifluoperazine, Thiothixene, Haloperidol, Loxapine, Molindone,Clozapine, Risperidone, Olanzapine, Quetiapine, Haloperidol decanoate,Fluphenazine decanoate, Fluphenazine enanthate, Amitriptyline,Amoxapine, Bupropion, Bupropion SR, Clomipramine, Desipramine, Doxepin,Fluoxetine, Fluvoxamine, Imipramine, Maprotiline, Mirtazapine,Nefazodone, Nortriptyline, Paroxetine, Phenelzine, Protriptyline,Sertraline, Tranylcypromine, Trazodone, Trimipramine , Venlafaxine,Velafaxine XR, Dextroamphetamine, Methamphetamine, Methylphenidate,Pemoline, Donepezil, Tacrine, Acetoplenazine, Chlorprothixene,Droperidol, Pimozide, Butaperazine, Carphenazine Remoxipride,Piperacetazine, Sulpiride, and Ziprasidone.
 4. A method for treating aneuropsychiatric disorder characterized by attenuated NMDAneurotransmission in a patient, the method comprising identifying apatient suffering from the neuropsychiatric disorder and administeringto the patient a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound selected from the group consisting ofD-phosphoserine and L-phosphoserine.
 5. The method of claim 4, whereincompound is administered at a dosage equivalent to 100 μg-100 g ofD-serine.
 6. The method of claim 4, wherein the compound is administeredat a dosage equivalent to 10 mg to 100 g of D-serine.
 7. The method ofclaim 4, where the compound is administered at a dosage equivalent to 1mg-100 mg of D-serine.
 8. The method of claim 4, wherein the compound isadministered at a dosage equivalent to 10 mg-10 g of D-serine.
 9. Themethod of claim 4, wherein the compound is administered at a dosageequivalent to 10 mg-500 mg of D-serine.
 10. The method of claim 4,further comprising administering to the patient a second therapeuticagent selected from the group consisting of antipsychotics,antidepressants, psychostimulants, and Alzheimer's disease therapeutics.11. The method of claim 4, wherein the compound is D-phosphoserine. 12.The method of claim 4, wherein the compound is L-phosphoserine.
 13. Themethod of claim 4, wherein the neuropsychiatric disorder is selectedfrom the group consisting of Alzheimer's disease, autism, depression,benign forgetfulness, a childhood learning disorder, attention deficitdisorder, and close head injury.
 14. The method of claim 4, wherein thecompound is administered to the patient by a method selected from thegroup consisting of oral, intravenous, trans-mucosal, nasal, vaginal,pulmonary, transdermal, ocular, buccal, sublingual, intraperitoneal,intrathecal, intramuscular, or long term depot preparation.
 15. A methodof treating schizophrenia, the method comprising identifying a patienthaving schizophrenia and treating the patient with a therapeuticallyeffective amount of a precursor of a compound selected from the groupconsisting of D-phosphoserine and L-phosphoserine.
 16. The method ofclaim 15, wherein the compound is administered at a dosage equivalent to100 μg-100 g of D-serine.
 17. The method of claim 15, wherein thecompound is administered at a dosage equivalent to 1 mg-100 mg ofD-serine.
 18. The method of claim 15, wherein the compound isadministered at a dosage equivalent to 10 mg-100 g of D-serine.
 19. Themethod of claim 15, wherein the compound is administered at a dosageequivalent to 10 mg-10 g of D-serine.
 20. The method of claim 15,wherein the compound is administered at a dosage equivalent to 10 mg-500mg of D-serine.
 21. The method of claim 15, wherein the compound isD-phosphoserine.
 22. The method of claim 15, wherein the compound isL-phosphoserine.
 23. The method of claim 15, wherein the compound isadministered to the patient by a method selected from the groupconsisting of oral, intravenous, trans-mucosal, nasal, vaginal,pulmonary, transdermal, ocular, buccal, sublingual, intraperitoneal,intrathecal, intramuscular, or long term depot preparation.